Peptide conjugated oligonucleotides for a phase I/IIa clinical trial in Spinal Muscular Atrophy

用于脊髓性肌萎缩症 I/IIa 期临床试验的肽缀合寡核苷酸

• 批准号: MR/R025312/1
• 负责人: Matthew Wood
• 金额: $ 272.08万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR025312%2F1
• 关键词: Peptide; conjugated; oligonucleotides; phase; IIa

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, arising from loss-of-function of the SMN1 gene. Mutations in SMN1 result in motor neuron degeneration, accompanied by peripheral manifestations including skeletal muscle atrophy. SMA is rare autosomal recessive disease with an incidence of ~1:10,000 live births. Most affected SMA infants typically have a severe form of the disease with a mean life expectancy of ~2 years in age (SMA Type I). However children with less severe disease (SMA Type II and III) can survive beyond 2 years but with severe mobility problems and comorbidities (respiratory insufficiency; scoliosis; failure to thrive) that limit normal functioning and survival. SMA severity relates directly to the level of functional SMN protein that a patient produces. A closely related gene to SMN1 is SMN2, although this gene typically only produces ~10% of fully functional SMN protein. However some SMA patients have additional copies of the SMN2 gene as the copy number of this latter gene is polymorphic in the general population, and hence can produce more functional SMN protein. This mitigates disease severity and such patients typically have a milder disease course. Most SMN2 gene product is not functional because the gene generates two distinct mRNAs via alternative splicing i.e. most of the mRNA lacks exon 7 and generates only partially functional protein. The most effective therapy currently for SMA is splice modification of the SMN2 pre-mRNA through use of SPLICE SWITCHING OLIGONUCLEOTIDES (SSOs) to increase levels of SMN protein. SSOs are single-stranded, DNA-like molecules that can bind to and alter the processing of SMN2 pre-mRNA to generate functional copy of the gene. A SSO (Nusinersen) which modifies SMN2 splicing to generate functional SMN protein has recently been approved for clinical use by the FDA and EMA. While this represents a major development for SMA, this first generation SSO does not penetrate the blood brain barrier (BBB) and is therefore administered through repeated invasive intrathecal injections into the fluid around the spinal cord. This is necessary for adequate spinal cord drug delivery but is not practical as a long-term therapy and moreover it also fails to treat systemic features of the disease, especially important in severe cases.The major challenge to successful development of an SSO therapy for SMA is systemic delivery of the SSO drug to all affected tissues involved in disease pathogenesis in addition to motor neurons, including peripheral tissues such as skeletal muscle and neuromuscular junctions, liver and autonomic nerves. We have developed a novel platform technology based on short cell penetrating peptides, which when attached to SSOs via direct chemical attachment provide highly effective penetration into cells and into tissues such as the brain and spinal cord and muscles which are exceptionally difficult to reach for large SSO drugs.The major OBJECTIVE of the current project is therefore to identify, develop and test an advanced NEXT GENERATION peptide-SSO for SMA. To achieve this we will:- Select the most suitable peptide based on further study of ~5 peptide-SSO candidates to determine their activity and safety properties in mice- Take this lead peptide-SSO and carry out a full safety assessment of the drug in two species (rats and non-human primates) as required by the Medicines and Healthcare Regulatory Agency, in order to obtain approval to undertake a clinical trial in SMA patients - Carry out a first-in-man phase I/IIa clinical trial in 12 less severely affected Type II and III SMA patients, who represent the most prevalent SMA patients, many of whom are not eligible candidates for intrathecal administration of drugs due to spinal abnormalities. This clinical trial will determine safety and inital effectiveness of the drug and will be a prelude to more detailed studies in larger numbers of patients

脊髓性肌萎缩症(SMA)是婴儿死亡的主要遗传原因，由SMN1基因功能丧失引起。SMN1基因突变会导致运动神经元变性，并伴有包括骨骼肌萎缩在内的外周表现。SMA是一种罕见的常染色体隐性遗传病，发病率约为1：10,000活产儿。大多数受影响的SMA婴儿通常患有严重的疾病，平均预期寿命为~2岁(SMA I型)。然而，病情较轻的儿童(SMA II型和III型)可以存活2年以上，但有严重的活动问题和限制正常功能和生存的共病(呼吸功能不全、脊柱侧弯、发育不良)。SMA的严重程度与患者产生的功能性SMN蛋白水平直接相关。与SMN1密切相关的基因是SMN1，尽管该基因通常只产生约10%的全功能SMN蛋白。然而，一些SMA患者有额外的SMN2基因拷贝，因为后者的拷贝数在普通人群中是多态的，因此可以产生更多功能的SMN蛋白。这减轻了疾病的严重性，而且这类患者的病程通常较轻。大多数SMN2基因产物没有功能，因为该基因通过选择性剪接产生两个不同的mRNAs，即大多数mRNAs缺少外显子7，只产生部分功能蛋白。目前对SMA最有效的治疗方法是通过剪接开关寡核苷酸(SSOs)剪接修饰SMN2pre-mRNAs来增加SMN蛋白的水平。SSO是一种单链、类似DNA的分子，可以与SMN2前-mRNA结合并改变其加工过程，以产生基因的功能副本。一种通过修改SMN2剪接来产生功能性SMN蛋白的SSO(Nusinesen)最近已被FDA和EMA批准用于临床。虽然这是SMA的一项重大发展，但这种第一代SSO不会穿透血脑屏障(BBB)，因此是通过反复向脊髓周围的液体中有创性鞘内注射来给药的。这对于充分的脊髓药物输送是必要的，但作为长期治疗是不可行的，而且它也不能治疗疾病的全身特征，在严重情况下尤其重要。成功开发SSO疗法治疗SMA的主要挑战是将SSO药物系统性地输送到除运动神经元之外的所有涉及疾病发病机制的受影响组织，包括周围组织，如骨骼肌和神经肌肉接头、肝脏和自主神经。我们开发了一种基于短细胞穿透肽的新型平台技术，当它通过直接化学连接到SSO上时，可以高效地渗透到细胞以及脑、脊髓和肌肉等组织中，而这些组织是大型SSO药物特别难以到达的。因此，本项目的主要目标是识别、开发和测试一种先进的用于SMA的下一代多肽-SSO。为了实现这一目标，我们将：-根据对~5肽-SSO候选者的进一步研究选择最合适的肽，以确定其在小鼠中的活性和安全性--采用这种先导肽-SSO，并按照药品和医疗保健监管机构的要求，对两种物种(大鼠和非人类灵长类动物)的药物进行全面的安全性评估，以获得在SMA患者中进行临床试验的批准-在12名受影响较轻的II型和III型SMA患者中进行第一人I/IIa期临床试验，这12名患者代表了最常见的SMA患者，其中许多人由于脊柱异常而不符合鞘内给药的条件。这项临床试验将确定该药物的安全性和初始有效性，并将是在更多患者中进行更详细研究的前奏。

项目成果

Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy.

• DOI: 10.1172/jci.insight.154142
• 发表时间: 2022-12-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Hammond SM;Abendroth F;Goli L;Stoodley J;Burrell M;Thom G;Gurrell I;Ahlskog N;Gait MJ;Wood MJ;Webster CI
• 通讯作者: Webster CI

Evaluation of Cell-Penetrating Peptide Delivery of Antisense Oligonucleotides for Therapeutic Efficacy in Spinal Muscular Atrophy.

• DOI: 10.1007/978-1-4939-9670-4_13
• 发表时间: 2019
• 期刊: Methods in molecular biology
• 作者: S. Hammond;F. Abendroth;M. Gait;M. Wood

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

通过 AAV8-Spc5-12 构建体过度表达 Klf15 对脊髓性肌萎缩症小鼠没有益处

• DOI: 10.1101/717785
• 发表时间: 2019
• 作者: Ahlskog N

Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy.

• DOI: 10.1172/jci.insight.149446
• 发表时间: 2021-07-08
• 期刊: JCI insight
• 影响因子: 8
• 作者: Meijboom KE;Volpato V;Monzón-Sandoval J;Hoolachan JM;Hammond SM;Abendroth F;de Jong OG;Hazell G;Ahlskog N;Wood MJ;Webber C;Bowerman M
• 通讯作者: Bowerman M

Delivery of oligonucleotide-based therapeutics: challenges and opportunities.

• DOI: 10.15252/emmm.202013243
• 发表时间: 2021-04-09
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Hammond SM;Aartsma-Rus A;Alves S;Borgos SE;Buijsen RAM;Collin RWJ;Covello G;Denti MA;Desviat LR;Echevarría L;Foged C;Gaina G;Garanto A;Goyenvalle AT;Guzowska M;Holodnuka I;Jones DR;Krause S;Lehto T;Montolio M;Van Roon-Mom W;Arechavala-Gomeza V
• 通讯作者: Arechavala-Gomeza V